This invention is generally in the field of anesthesiology and, in particular, the non-systemic or localized administration of non-steroidal anti-inflammatory drugs to traumatized tissue for the treatment of localized pain.
Pain can be defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is a complex process influenced by both physiological and psychological factors. Pain is typically subjective and many health care professionals are not trained to effectively assess or treat pain. The management of pain, particularly post-surgical pain, is most often based on the systemic administration of pain relieving drugs.
The three major classes of pharmaceutical drugs used to treat post-surgical pain are the opiates, local anesthetics, and the non-steroidal anti-inflammatory drugs (NSAID). Two of these classes of drugs, the opiates and NSAIDs, are typically administered systemically while the local anesthetics (e.g. channel blockers) are administered non-systemically during surgery. The systemic administration of drugs to relieve pain after surgery is frequently inadequate. For example, systemic administration of opiates after surgery may cause nausea, the inhibition of bowel function, urinary retention, inhibition of pulmonary function, cardiovascular effects, and sedation. When NSAIDs are given systemically, there is a potential for gastrointestinal (GI) and renal side effects as well as inhibition of platelet function.
The effectiveness of NSAIDs on traumatized tissue during the inflammatory period of wound healing combined with their “opiate sparing” ability and weak central analgesic effect make them ideal potential candidates for non-systemic or localized administration to traumatized tissue for the reduction of localized pain, as recognized for example in US 2003/0118651. As used herein, the term “non-systemic” refers to the application of a composition or drug to the site of a traumatized tissue, intracorporeally at a surgical wound site or a trauma site, or topically, i.e., internally and/or externally. The terms “surgical wound site” and “trauma site” are meant to include the site of tissue that has been injured in any way, and includes, for example, tissue sites that have undergone incision, drying, suturing, excision, abrasion, contusion, laceration, anastomosis, manipulation, prosthetic surgery, curettage, orthopedic surgery, neurosurgery, cardiovascular surgery, or plastic or reconstructive surgery. The treatment is intended to be “locally effective”, that is the treatment is intended to affect only the tissue treated or adjacent or neighboring tissue.
There are numerous references generally describing the administration of NSAIDs via drug delivery systems that may be utilized non-systemically. The efficacy of various NSAIDs for the treatment of post-surgical pain are also reported in many of these references. These systems typically consist of a polymeric matrix or liposome from which drug is released by diffusion and/or degradation of the matrix. The release pattern is usually principally determined by the matrix material, as well as by the percent of loading, method of manufacture, type of drug being administered and type or geometry of the device. Often the drug delivery system is biocompatible and absorbable, which permits it to be used intracorporeally at the surgical wound site or trauma site and then slowly absorbed by the patient's body. One advantage of using an absorbable drug delivery system at the surgical wound site or trauma site is that the site does not have to be re-opened to remove the drug delivery system after depletion of the drug.
For example, U.S. Pat. No. 4,937,254 teaches that NSAIDs can be administered non-systemically and intercorporeally to a surgical wound site or trauma site via incorporation of the NSAID and a pharmaceutically acceptable carrier such as hyaluronic acid, chitosan, and liposome, directly at the site of the traumatized tissue. Examples of the NSAID include ibuprofen, suprofen or tolmetin. This reference describes the efficacy of such NSAIDs for inhibiting post-surgical adhesions, but not for reducing post-surgical localized pain.
U.S. Pat. No. 5,888,523 describes a NSAID composition that may be used for the non-systemic treatment of pain associated with inflamed/irritated tissue. Specifically, this reference is directed to the use of an aqueous based carrier system for NSAIDs for topical application on the inflamed/irritated tissue. In particular, the system described in this reference consists of a water dispersible natural cellulosic polymer, an organic acid, and an NSAID. This reference specifically reports the efficacy of naproxen and ibuprofen for the treatment pain associated with vulvodynia or vulvar vestibulitis, and suggests that drugs such as indomethacin, diclofenac and ketoprofen may also be used. This reference does not describe, suggest or predict the efficacy of the NSAID system when used intracorporeally at a surgical wound site or trauma site for the non-systemic treatment of localized pain associated therewith.
Although the prior art reports the efficacy of a naproxen or ibuprofen system for the treatment pain associated with vulvodynia or vulvar vestibulitis (via topical application), and suggests that systems containing drugs such as indomethacin, diclofenac and ketoprofen are efficacious for the treatment pain associated with vulvodynia or vulvar vestibulitis (via topical application) in U.S. Pat. No. 5,888,523; such results and suggestions are not predictive of the efficacy of, for example, an indomethacin, diclofenac or ketoprofen system when administered non-systemically and intercorporeally at the site of a surgical wound or trauma, for the reduction of localized pain at the site. As the clinical requirement for a drug delivery carrier of any given therapeutic agent for intercorporeal application at a surgical wound site or a trauma site is much more demanding than for topical application of the same therapeutic agent, there is usually no predictive correlation between non-systemic topical application and non-systemic intercorporeal application at a surgical wound site or a trauma site of a particular NSAID system. In addition to drug-carrier compatibility, critical factors to consider for a drug delivery carrier for use in intercorporeal application at a surgical wound site or a trauma site include, but is not limited to, tissue reaction, biocompatibility, bioabsorbability, biodegradability, and mechanical strength. For example, one would not expect the mechanical properties of the NSAID composition disclosed in U.S. Pat. No. 5,888,523 to be suitable for intercorporeal use at a surgical wound site or a trauma site, because the NSAID composition is based on a water dispersible cellulosic polymer that is not expected to remain in the fluid environment of the body for a long enough period of time to allow for release of the NSAID. Additionally, according to the material safety data sheet (MSDS), small organic acids such as citric acid, acetic acid, maleic acid and lactic acids may cause undesired health hazards, for instance, skin irritation, respiratory tract irritation, allergic reactions and mucos membrane burns. The presence of an organic acid in the NSAID composition renders its biologically incompatible with a surgical wound site or a trauma site, even possibly causing tissue irritation that may be detrimental to wound healing.
As described above, NSAID's are ideal potential candidates for non-systemic or localized administration to traumatized tissue for the reduction of localized pain. Therefore, it is desirable to have a NSAID drug delivery system that is efficacious when administered non-systemically and intercorporeally at the site of a surgical wound or trauma, for the reduction of localized pain at the site.